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Abstract Background Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. Methods The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-β1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-β1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. Results CCl4 exposure or TGF-β1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-β1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-β1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. Conclusion GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

Abstract Background Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. Methods To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. Results Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). Conclusions Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity. Graphical Abstract

Abstract Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder affecting millions of adults worldwide, but a poor understanding of its pathogenesis has limited the effectiveness of therapy. In the current study, we integrated untargeted LC/MS metabolomics and magnetic resonance spectroscopy data to investigate metabolic profile alterations during IDD. Combined with validation via a large-cohort analysis, we found excessive lipid droplet accumulation in the nucleus pulposus cells of advanced-stage IDD samples. We also found abnormal palmitic acid (PA) accumulation in IDD nucleus pulposus cells, and PA exposure resulted in lipid droplet accumulation and cell senescence in an endoplasmic reticulum stress-dependent manner. Complementary transcriptome and proteome profiles enabled us to identify solute carrier transporter (SLC) 43A3 involvement in the regulation of the intracellular PA level. SLC43A3 was expressed at low levels and negatively correlated with intracellular lipid content in IDD nucleus pulposus cells. Overexpression of SLC43A3 significantly alleviated PA-induced endoplasmic reticulum stress, lipid droplet accumulation and cell senescence by inhibiting PA uptake. This work provides novel integration analysis-based insight into the metabolic profile alterations in IDD and further reveals new therapeutic targets for IDD treatment.

Abstract Objectives The objectives of this study were to evaluate the cost-effectiveness and cost-benefit of fluoride varnish (FV) interventions for preventing caries in the first permanent molars (FPMs) among children in rural areas in Guangxi, China. Methods This study constituted a secondary analysis of data from a randomised controlled trial, analysed from a social perspective. A total of 1,335 children aged 6–8 years in remote rural areas of Guangxi were enrolled in this three-year follow-up controlled study. Children in the experimental group (EG) and the control group (CG) received oral health education and were provided with a toothbrush and toothpaste once every six months. Additionally, FV was applied in the EG. A decision tree model was developed, and single-factor and probabilistic sensitivity analyses were conducted. Results After three years of intervention, the prevalence of caries in the EG was 50.85%, with an average decayed, missing, and filled teeth (DMFT) index score of 1.12, and that in the CG was 59.04%, with a DMFT index score of 1.36. The total cost of caries intervention and postcaries treatment was 42,719.55 USD for the EG and 46,622.13 USD for the CG. The incremental cost-effectiveness ratio (ICER) of the EG was 25.36 USD per caries prevented, and the cost–benefit ratio (CBR) was 1.74 USD benefits per 1 USD cost. The results of the sensitivity analyses showed that the increase in the average DMFT index score was the largest variable affecting the ICER and CBR. Conclusions Compared to oral health education alone, a comprehensive intervention combining FV application with oral health education is more cost-effective and beneficial for preventing caries in the FPMs of children living in economically disadvantaged rural areas. These findings could provide a basis for policy-making and clinical choices to improve children’s oral health.

The deep coal mining in China is becoming more and more complicated. Under the influence of mining, structure or hard roof and floor, the section coal pillar is easy to induce coal pillar type rock burst. The prevention and control of coal pillar type rock burst has become a difficult problem in coal mine safety and efficient mining. It is of positive significance to study the mechanical properties and impact failure characteristics of section coal pillars under different width-height ratio for the prevention and control of coal pillar type rock burst. Uniaxial compression experiments were carried out on the “rock-coal-rock”combination of coal samples with different width-height ratio. The influence of width-height ratio on the impact failure of coal pillars was studied by analyzing the impact tendency, dynamic failure characteristics, fractal dimension and acoustic emission characteristic parameters of the combination. The results show that: ① The width-height ratio of coal pillar has a significant effect on the impact tendency of the combination. When the width-height ratio is not less than 2∶1, the impact energy index KE is 1.82−2.65, and the impact tendency has no obvious change. When is less than 2∶1, the impact tendency increases first and then decreases. When is 1∶1, KE is the largest, reaching 15.43. ② With the decrease of width-height ratio, the failure characteristics of the composite body are as follows: tension-compression failure-compression-shear failure-tension-shear failure. When the width-height ratio of the coal pillar is 5∶1−3∶1, the damage of the combination is relatively slow. When the width-height ratio is 2∶1, the flake coal chips begin to pop out, and the degree of impact damage is low. When the width-height ratio is 1∶1 and 0.75∶1, it has obvious impact failure characteristics. When the width-height ratio is 0.5∶1, the overall stability of the combination decreases, and the severity of the coal pillar failure of the 0.75∶1 sample combination decreases. ③ The energy release rate of post-peak acoustic emission is similar to that of fractal dimension D, which increases first and then decreases with the decrease of width-height ratio. When the width-height ratio is not less than 2∶1, the energy release time is longer during the failure process of the combination, and the coal pillar failure is gentle. When the width-height ratio is 1∶1, the energy release rate and D value increase significantly. Compared with the energy release rate of the combination with a width-height ratio of not less than 2∶1, the energy release rate increases by about 4 times, and the D value increases by 0.18−0.23. The impact damage of coal pillar is the most severe. The energy release rate and D value of the 0.75∶1 combination were reduced by about 10% and 0.01, respectively, and the damage severity was similar to that of the 1∶1 combination. When the width-height ratio is reduced to 0.5∶1, the reduction of the relevant parameters is about 6 times that of the 0.75∶1 combination, and the degree of damage is relatively small.The results show that the width-height ratio has a significant effect on the impact failure of coal pillars. On the whole, the intensity of impact failure of coal pillars increases first and then decreases gradually with the decrease of width-height ratio (5∶1−0.5∶1). When the width-height ratio of coal pillar is greater than 3∶1, the rock burst risk is relatively small. When the width-height ratio of coal pillar is 1∶1 and 0.75∶1, the rock burst risk is larger, followed by 0.5∶1.

In order to expand the relevant theory of fractional differential equation systems, a class of coupled φ-Hilfer fractional differential systems with integral boundary conditions was studied. Firstly, the coupled φ-Hilfer fractional differential system with integral boundary conditions was transformed into an integral system. Secondly, the appropriate Banach product space and norm were defined, the appropriate integral operator was constructed, and the existence result of the solution of the coupled φ-Hilfer fractional differential system under the integral boundary condition was given by using the compressed image principle and Kransnoselskii's fixed point theorem, respectively. Finally, examples were given to illustrate the correctness of the conclusions obtained. The results show that the solutions of the coupled φ-Hilfer fractional differential system under the integral boundary condition exist. The existence of solutions of coupled φ-Hilfer fractional differential systems is studied for the first time by using the compressed image principle and Kransnoselskii's fixed point theorem, respectively, and some innovative new results are obtained. In addition, the research conclusion enriches the relevant theories of the theoretical solvability of coupled fractional differential systems, and provides certain theoretical reference value for the further study of fractional order differential equations.

On April 3, 2024, at 07:58 (Beijing time), a magnitude 7.3 earthquake occurred in the waters of Hualien County, Taiwan Province. The Institute of Geophysics, China Earthquake Administration initiated a rapid response after the earthquake and organized geophysics researchers to estimate the source model and seismic radiation energy of the earthquake. Based on the source model, the shakemap and coseismic deformation field simulation were carried out. The results indicate that the earthquake occurred at the boundary between the Philippine Sea Plate and the Eurasian Plate, primarily characterized by a thrust mechanism, with energy released predominantly in the first 35 seconds. The earthquake intensity in the extreme seismic area possibly have reached more than X degree, with a potential disaster area of approximately 35000 km2. The earthquake also caused significant coseismic displacements, with the maximum horizontal displacement reaching 0.52 m and the vertical displacement reaching 1.18 m.

Abstract The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10−8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10−14; 543 patients) and 1.80 (P = 1.11 × 10−9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

On January 23，2024 at 02:09 (Beijing time), the MS7.1 earthquake occurred in Wushi county, Aksu Prefecture, Xinjiang. The Institute of Geophysics, China Earthquake Administration initiated a rapid response after the earthquake, organized researchers in related fields to estimate the source parameters, seismic radiation energy, and repositioned the aftershock sequence. At the same time, seismic map simulation and co-seismic deformation field simulation were carried out based on the source model. The results indicate that the earthquake occurred within the Tianshan Mountains, mainly through a thrust mechanism, with energy concentrated and released within the first 25 seconds; The seismic intensity in the extreme earthquake zone may reach over Ⅸ degrees, with a possible disaster area of nearly 65000 km2; This earthquake caused significant coseismic displacement, with a maximum horizontal displacement of 21 cm and a vertical displacement of 38 cm.

Abstract Background Type 2 diabetes mellitus (T2DM) causes severe bone loss after tooth extraction as a hyperglycemic environment causes aberrant bone homeostasis. Artesunate (ART) is known to possess anti-inflammation and osteogenic properties. However, its osteogenesis property in alveolar bone remains unclear. This study aimed to explore the osteogenic and immunoregulatory effects of artesunate-loaded thermosensitive chitosan hydrogel (ART-loaded TCH) on maxilla tooth extraction in T2DM rats. Methods T2DM rats were induced by a high-fat diet and streptozotocin. Different concentrations of ART-loaded TCH were applied in tooth extraction sockets. Bone loss and the expression of osteogenic regulatory factors (OPG, ALP, RANK) were evaluated. The immunoregulatory effects of ART-loaded TCH were observed through detecting the infiltration of T lymphocytes and their cytokines. The underlying mechanisms were explored. Results Results showed that the 150 mg/ml ART-loaded TCH group significantly ameliorated maxilla bone height and bone mineral density when compared with the T2DM group (p

Abstract Background Although previous studies have found that parenting style significantly predicts emotional and behavioral problems (EBPs) among Chinese adolescents, the mechanism between different parenting styles and EBPs requires in-depth investigation. In our study, we aimed to investigate the mediating effect of resilience, a positive psychological characteristic, between parenting style and EBPs among Chinese adolescents. Methods In this cross-sectional study, we used a multistage stratified cluster random sampling method to collect data in Shenyang, Liaoning Province from November to December 2019. Self-developed questionnaires were distributed to 1028 adolescents aged 10–18. Finally, the study consisted of 895 participants. The bootstrap method was used to investigate the role of resilience as a mediator in the relationship between different parenting styles and EBPs from a positive psychology perspective. Results The mean score of EBPs was 12.71 (SD = 5.77). After controlling for variables such as gender, age, left-behind children, family type and family income, resilience partially played a mediating role in the associations of paternal rejection (a × b = 0.051 BCa95%CI:0.023,0.080), maternal rejection (a × b = 0.055 BCa95%CI: 0.024, 0.086), paternal emotional warmth (a × b = -0.139 BCa95%CI: -0.182, -0.099) and maternal emotional warmth (a × b = -0.140 BCa95%CI: -0.182, -0.102), with EBPs. The effect sizes were11.28%, 11.51%, 40.76%, and 38.78%, respectively. Conclusions Resilience could partially mediate the relationship between parenting style and EBPs, highlighting that parents should adopt a positive parenting style and that resilience improvement could be effective in reducing EBPs among Chinese adolescents.

Based on the simulation results of ProCAST software for the filling and solidification process, the formation mechanism of the VIM electrode ingot's pipe and porosities and the influence of the casting process on the formation of electrode shrinkage were studied in detail. The research results indicate that the critical condition for the formation of 200 kg grade C650R heat-resistant alloy is verified to be G/R≤5.0 (K·s)0.5/cm. In addition to the alloy's inherent characteristics, the substantial height to diameter ratio (H/D) of the VIM electrode ingot is the primary factor contributing to the formation of deep pipe and severe porosities. Simply adjusting the casting time or casting speed alone does not significantly improve the solidification quality of the ingot. While the use of a hot top can eliminate pipe, its effectiveness is limited, as the alloy melt at the hot top location has minimal influence on the solidification process in the lower regions of the electrode ingot, thereby failing to effectively reduce the formation of porosities. Properly reducing the casting speed and casting superheat lead to the formation of a V-shaped melt at localized positions during the final stage of solidification. This enhances the ability of the liquid phase for further feeding, ultimately significantly decreasing both the depth of pipe and the porosity rate. The optimal casting process optimization solution for C650R alloy electrode ingot with a size of Φ130 mm × 1240 mm is the casting speed of 60 kg/min and the superheat of 40 °C.

Sorafenib is a first-line drug for liver cancer treatment, but its clinical efficacy is still limited by drawbacks such as drug tolerance, toxic effects, and low bioavailability. Therefore, it is urgent to find efficient ways to synergize sorafenib with other agents and increase its bioavailability in order to enhance its clinical efficacy. Herein, we report the successful development of a carrier-free nanoplatform of an artesunate prodrug to potentiate the efficacy of sorafenib against hepatocellular carcinoma. The artesunate prodrug was synthesized by conjugating artesunate and linoleic acid through a thioketone (TK) bond. This prodrug can self-assemble in an aqueous solution via a one-step precipitation method. Furthermore, the inclusion of sorafenib during the self-assembly process results in a carrier-free artesunate/sorafenib mixed nanomedicine (SA@NPs) with a uniform and stable particle size. In addition, SA@NPs possess ROS-responsive drug-releasing ability by breaking up thioketone bonds under high H2O2 levels in tumors. The synergistic anticancer effects of SA@NPs have been demonstrated both in vivo and in vitro. SA@NPs can achieve significantly enhanced synergetic ferroptosis of tumor cells and show potentiated sorafenib efficacy against hepatocellular carcinoma. Moreover, SA@NPs have a tumor inhibition rate of 84.2%, which is 1.63-, 4.22-, and 1.29-fold higher than that in the experimental groups treated with free sorafenib, artesunate, and the simplified combined medication of sorafenib/artesunate, respectively. Overall, this work presents a significant advancement in the clinical chemotherapy of liver cancer and may pave the way for promising developments in the compatibility and clinical combination application of traditional Chinese medicine.

Abstract Clamping bushing structure is an internode connection mechanism designed for the standard section of tubular truss tower. In this paper, the clamping bushing structure of the connecting mechanism of super-large tower crane is taken as the research object, a three-dimensional model of clamping bushing structure is established and imported into ABAQUS, and its multi-body contact model is further constructed to study the contact and bearing relationship of the structure under multiple working conditions, and the accuracy of the calculation results of the model is verified by the experimental stress test under tensile working conditions. In addition, this study is based on the control variable method, and through the design of orthogonal test table, the influence degree of five variable parameters of clamping bushing on the bearing capacity of the structure is investigated. Finally, through the range analysis, the optimal horizontal combination of variables and parameters of clamping bushing structure is obtained, and the optimal matching relationship between the shape of the tower connecting mechanism and the bearing capacity is obtained. The results show that, compared with the original model, the stress concentration at the most dangerous section of the optimized joint and the bushing is obviously alleviated, in which the stress peaks of the upper and lower joints are kept below 500 MPa, and the stress peaks of the bushing groove are also reduced to between 573 and 722 MPa. Moreover, the designed and optimized lower joint can reduce the maximum equivalent plastic strain of the joint root circumference by 56.05% under the original maximum tensile condition, and the overall distribution trend of equivalent plastic strain is more uniform, and a more reliable structural design is obtained, which plays an important guiding role in the design, optimization and analysis of the connecting mechanism of the tower body of large tower crane.

Abstract Background Environmental factors play an important role in developing mental disorders. This study aimed to investigate the associations of metal and nonmetal elements in drinking water with the risk of depression and anxiety and to assess whether diets modulate these associations. Methods We conducted a prospective cohort study including 24,285 participants free from depression and anxiety from the Yinzhou Cohort study in the 2016–2021 period. The exposures were measured by multiplying metal and nonmetal element concentrations in local pipeline terminal tap water samples and total daily drinking water intakes. Cox regression models adjusted for multi-level covariates were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (95%CIs). Results During an average follow-up period of 4.72 and 4.68 years, 773 and 1334 cases of depression and anxiety were identified, respectively. A 1 standard deviation (SD) increase in manganese exposure reduced the incidence of depression by 8% (HR 0.92, 95%CI 0.88 to 0.97). In contrast, with a 1 SD increase in copper and cadmium exposure, the incidence of depression increased by 6% (HR 1.06, 95%CI 1.01 to 1.11) and 8% (HR 1.08, 95%CI 1.00 to 1.17), respectively. The incidence of anxiety increased by 39% (HR 1.39, 95%CI 1.20 to 1.62), 33% (HR 1.33, 95%CI 1.03 to 1.71), and 14% (HR 1.14, 95%CI 1.03 to 1.25) respectively for a 1 SD increase in manganese, iron, and selenium exposure. Diets have a moderating effect on the associations of metal and nonmetal elements with the risk of anxiety. Stronger associations were observed in older, low-income groups and low-education groups. Conclusions We found significant associations between exposure to metal and nonmetal elements and depression and anxiety. Diets regulated the associations to some extent.

Abstract Background In the global trend of actively promoting the participation of older adults in the digital age, the relevant negative issues featuring potential Internet Addiction (IA) among them has risen to be a new challenge facing the global public health. However, there is a severe lack of related research. This study aimed to gain a comprehensive understanding of the phenomenon and process of IA among the elderly. The purpose of this paper is to introduce factors that may influence IA in the demographic. Methods This study employed qualitative descriptive research methods to investigate older adults’ perceptions and experiences of IA. Semi-structured in-depth personal interviews were conducted between March and June 2023 with 36 senior citizens from urban communities in Chongqing, Southwest China. Data were analyzed via inductive content analysis methods. Results Through data analysis, 2 main categories concerning IA in older adults were identified: risk factors and protective factors. The risk factor categories include 5 individual factors (e.g., Internet as the major avenue for pursuing personal hobbies and interests, etc.), 3 family factors (e.g., household WIFI increasing the risk of prolonged Internet use indoors, etc.), 2 peer factors (e.g., peer recommendation and guidance as catalysts for intensified Internet engagement, etc.), 2 socio-environmental factors (e.g., the widespread daily Internet use spurs offline intolerance, etc.), and 3 Internet platform factors (e.g., the plenitude of online content triggers endless viewing/browsing behaviors, etc.). The category of protective factors encompasses 2 individual factors (e.g., a higher level of perceived risk regarding internet health hazards, etc.) and 2 family factors (e.g., more family commitment, etc.). Conclusions Older adults’ Internet addictive behaviors are shaped by multiple and complex internal and external factors. A higher level of online health risk perception is a key protective factor to effectively avoid the occurrence and deterioration of IA among the aged, a distinct finding from this study. It is believed that the “individual-family-peer-community” synergy strategy is expected to become an essential direction for IA intervention for older adults, in order to promote healthy Internet use among older adults.

At 22:37 on December 2, 2023 (Beijing time), a M7.6 earthquake occurred in the eastern waters of Mindanao，Philippines. The Institute of Geophysics, China Earthquake Administration initiated the response mechanism after this earthquake and organized geophysics researchers to estimate the source parameters, focal mechanism，rupture process and earthquake radiation energy of this earthquake. Based on the source model, the Shakemap and the coseismic deformation field simulation are carried out. Product results demonstrate that this earthquake occurred on the subduction zone slab where the Philippine Sea Plate collided with the Eurasian Plate/Sunda Block. This earthquake is of dominant thrusting mechanism. The energy was concentrated and released in the first 40 seconds. The maximum slip of the fault rupture is up to 7 m. The efficiency of the earthquake source in radiating seismic energy is low and the slowness coefficient is slightly lower than the average level of the global same moment magnitude earthquake, and the feeling of the earthquake is relatively weak. The earthquake intensity in the extreme seismic area possibly reaches more than Ⅸ, and the approximate disaster range is up to 27000 km2. This earthquake caused apparent coseismic displacement with the maximum displacements reaching 0.6 m and 1.2 m in the horizontal and vertical directions respectively. Comprehensive analysis shows that this earthquake can’t produce a large-scale tsunami.

Introduction This study aimed to assess the causal relationship between diabetes and frozen shoulder by investigating the target proteins associated with diabetes and frozen shoulder in the human plasma proteome through Mendelian randomization (MR) and to reveal the corresponding pathological mechanisms.Research design and methods We employed the MR approach for the purposes of establishing: (1) the causal link between diabetes and frozen shoulder; (2) the plasma causal proteins associated with frozen shoulder; (3) the plasma target proteins associated with diabetes; and (4) the causal relationship between diabetes target proteins and frozen shoulder causal proteins. The MR results were validated and consolidated through colocalization analysis and protein–protein interaction network.Results Our MR analysis demonstrated a significant causal relationship between diabetes and frozen shoulder. We found that the plasma levels of four proteins were correlated with frozen shoulder at the Bonferroni significance level (p

Arsenic (As) pollution in rice (Oryza sativa L.), a staple food for over 3.5 billion people, is a global problem. Mixed effects of Zn, Cu, and Si amendments on plant growth and yield, including in the presence of As pollution have been reported in previous studies. To better investigate the effectiveness of these amendments on rice growth, yield, and As accumulation, we conducted a rice greenhouse experiment with 11 treatments, including control pots with and without As contamination and pots with amendments of ZnO, CuO, and SiO2 nanoparticles (ZnO NPs, CuO NPs, and SiO2 NPs), their ionic counterparts (ZnSO4, CuSO4, and Na2SiO3), and bulk particles (ZnO BPs, CuO BPs, and SiO2 BPs). Compared with the background soil, the treatment of adding As decreased rice plant height, panicle number, and grain yield by 16.5%, 50%, and 85.7%, respectively, but significantly increased the As accumulation in milled rice grains by 3.2 times. Under As contamination, the application of Zn amendments increased rice grain yield by 4.6–7.3 times; among the three Zn amendments, ZnSO4 performed best by fully recovering grain yield to the background level and significantly reducing grain AsIII/total As ratio by 46.9%. Under As contamination, the application of Cu amendments increased grain yield by 3.8–5.6 times; all three Cu amendments significantly reduced grain AsIII/total As ratio by 20.2–65.6%. The results reveal that Zn and Cu amendments could promote rice yield and prevent As accumulation in rice grains under As contamination. Despite the observed reduction in As toxicity by the tested NPs, they do not offer more advantages over their ionic counterparts and bulk particles in promoting rice growth under As contamination. Future field research using a broader range of rice varieties, investigating various As concentrations, and encompassing diverse climate conditions will be necessary to validate our findings in achieving more extensive understanding of effective management of arsenic contaminated rice field.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. Pirfenidone (PFD) and nintedanib (NDN) were both conditionally recommended in the clinical practice guideline published in 2015. Safety and tolerability are related to the risk of treatment discontinuation. Therefore, this study evaluated and compared the adverse events (AEs) of PFD and NDN in a large real-world population by analyzing data from the FDA Adverse Event Reporting System (FAERS) to provide a reference for their rational and safe use.MethodsThe AEs of PFD and NDN were extracted from the FAERS database. The pharmacovigilance online analysis tool OpenVigil 2.1 was used to retrieve data from the FAERS database from the first quarter of 2012 to the second quarter of 2022. The reporting odds ratio (ROR) and proportional reporting ratio were used to detect the risk signals.ResultsThe database included 26,728 and 11,720 reports for PFD and NDN, respectively. The most frequent AEs of PFD and NDN were gastrointestinal disorders. The RORs for these drugs were 5.874 and 5.899, respectively. “Cardiac disorders” was the most statistically significant system order class for NDN with an ROR of 9.382 (95% confidence interval = 8.308–10.594). Furthermore, the numbers of designated medical events of PFD and NDN were 552 and 656, respectively. Notably, liver injury was reported more frequently for NDN (11.096%) than for PFD (6.076%).ConclusionThis study revealed differences in the reporting of AEs between PFD and NDN. The findings provide reference for physicians in clinical practice. Attention should be paid to the risks of cardiac disorders and liver injury associated with NDN.

BackgroundThere is evidence of a modest reduction in skin cancer risk among metformin users. However, no studies have further examined the effects of metformin on melanoma survival and safety outcomes. This study aimed to quantitatively summarize any influence of metformin on the overall survival (OS) and immune-related adverse effects (irAEs) in melanoma patients.MethodsSelection criteria: The inclusion criteria were designed based on the PICOS principles. Information sources: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for relevant literature published from the inception of these databases until November 2023 using ‘Melanoma’ and ‘Metformin’ as keywords. Survival outcomes were OS, progression-free survival (PFS), recurrence-free survival (RFS), and mortality; the safety outcome was irAEs. Risk of bias and data Synthesis: The Cochrane tool for assessing the risk of bias in randomized trial 2 (RoB2) and methodological index for non-randomized studies (MINORS) were selected to assess the risk of bias. The Cochrane Q and I2 statistics based on Stata 15.1 SE were used to test the heterogeneity among all studies. Funnel plot, Egger regression, and Begg tests were used to evaluate publication bias. The leave-one-out method was selected as the sensitivity analysis tool.ResultsA total of 12 studies were included, involving 111,036 melanoma patients. The pooled HR for OS was 0.64 (95% CI [0.42, 1.00], p = 0.004, I2 = 73.7%), HR for PFS was 0.89 (95% CI [0.70, 1.12], p = 0.163, I2 = 41.4%), HR for RFS was 0.62 (95% CI [0.26, 1.48], p = 0.085, I2 = 66.3%), and HR for mortality was 0.53 (95% CI [0.46, 0.63], p = 0.775, I2 = 0.0%). There was no significant difference in irAEs incidence (OR = 1.01; 95% CI [0.42, 2.41]; p = 0.642) between metformin and no metformin groups.DiscussionThe improvement in overall survival of melanoma patients with metformin may indirectly result from its diverse biological targets and beneficial effects on multiple systemic diseases. While we could not demonstrate a specific improvement in the survival of melanoma patients, the combined benefits and safety of metformin for patients taking the drug are worthy of recognition.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024518182.

Alzheimer’s disease (AD) is a progressive neurological disorder, with two main pathological hallmarks of senile plaques and neurofibrillary tangles accumulated of abnormally phosphorylated Tau. Ginkgolic acid (GA), as an inhibitor of SUMO-1, exhibits many biological activities, including neuroprotective effects. However, the efficacy of GA in AD treatment has not been sufficiently investigated. Therefore, the current study aimed to explore the function and the underlying molecular mechanisms of GA related to AD. Our study revealed that GA exerted protective effects on cognitive impairment of an Aβ-induced AD rat model, and suppressed the neuronal apoptosis and oxidative stress induced by Aβ1-42 both in vivo and in vitro. Of crucial importance, GA significantly inhibited Tau phosphorylation, and blocked the activation of the SUMO-1/GSK3β signaling pathway. Taken together, these observations demonstrated that GA improved cognitive ability and inhibited Tau phosphorylation through SUMO1/GSK3β pathway, indicating that GA is a potential drug for the preventing and treatment of AD.

Abstract Adventitious root formation is a key step in vegetative propagation via cuttings. It is crucial for establishing birch plantations and preserve birch varieties. Although previous studies have highlighted role of WOX11 in controlling adventitious root formation, no such study has been conducted in birch. Understanding the mechanism of adventitious root formation is essential for improvement of rooting or survival rate using stem cuttings in birch. In this study, we cloned BpWOX11 and produced BpWOX11 overexpression (OE) transgenic lines using the Agrobacterium-mediated plant transformation. OE lines exhibited early initiated adventitious root formation, leading to increase the rooting rate of stem cuttings plants. RNA sequencing analysis revealed that OE lines induced the gene expression related to expansin and cell division pathway, as well as defense and stress response genes. These may be important factors for the BpWOX11 gene to promote adventitious root formation in birch cuttings. The results of this study will help to further understand the molecular mechanisms controlling the formation of adventitious roots in birch.

AbstractCyperus malaccensis Lam is a perennial herbaceous plant that is distributed over a large area along the southern coast of China. Some plants of the Cyperaceae family are highly similar morphologically, which makes them difficult to classify and identify. In this study, the complete chloroplast genome of C. malaccensis was sequenced and assembled. The chloroplast genome is 186,098 bp long with a 33.18% content of GC. The structure of chloroplast genome includes a quadripartite structure that is composed of a pair of inverted repeats (IRs) of 37,434 bp, a small single copy (SSC) region of 10,296 bp, and a large single copy (LSC) region of 100,934 bp. The genome contains 141 genes, including 94 protein-coding genes, 39 tRNA genes, and 8 rRNA genes. A phylogenetic analysis showed that C. malaccensis is the most closely related to the congeneric species C. rotundus. These results enrich the genetic resources of the Cyperaceae and provide a molecular basis for further study on the phylogeny of this family.

At 23:59 on December 18, 2023 (Beijing time), a M6.2 earthquake occurred in the Gansu Province of Jishishan. The Institute of Geophysics，China Earthquake Administration initiated the response mechanism after this earthquake and organized geophysics researchers to estimate the source parameters, focal mechanism, rupture process, earthquake radiation energy and earthquake relocation of this earthquake. Based on the source model, the Shakemap and the coseismic deformation field simulation are carried out. The results demonstrate that the earthquake is of dominant thrusting mechanism. The energy was concentrated and released in the first 8 seconds. The earthquake intensity in the extreme seismic area possibly exceeded Ⅷ, resulting in an estimated disaster range of approximately 6000 km2. This earthquake caused apparent horizontal coseismic displacement with maximum displacements reaching 7.8 cm and 15.8 cm.

Abstract To evaluate the possible thermal risks associated with the storage of octogen (HMX), non-isothermal differential scanning calorimetry (DSC) experiments were conducted in order to ascertain the kinetic model and parameters governing its thermal decomposition. DSC measurements indicate that HMX underwent a crystal transformation prior to thermal decomposition. A kinetic model for the autocatalytic thermal decomposition process was developed through the analysis of its primary exothermic peaks. Subsequently, numerical simulations were performed using the aforementioned kinetic model to assess the potential thermal explosion hazard of HMX under two distinct storage conditions. The comparison was made between the models of HMX autocatalytic decomposition temperature and thermal explosion critical temperature under two distinct storage conditions. The prediction of the influence of ambient temperature on the critical temperature of thermal explosion is conducted simultaneously. Finally, the thermal hazard parameters of HMX under different package quality are given.

This is an essay in the field of mineral processing engineering. Based on the process mineralogy, a mixed process containing roasting-water quenching-hot pressure leaching was applied to purify a white pegmatite ore from Inner Mongolia. The optimum condition was obtained via various tests. The content of SiO2 in the final product was increased from 99.917% to 99.994%, while the total impurity content was decreased from 419.9 to 54.79 g/t, with a total removal of 86.95%. The main impurity element of Al was decreased from 250.9 g/t to 26.09 g/t, with a removal of 89.60%. Therefore, this study provides a good purification approach for high-purity quart preparation.

Abstract Target trial emulation is the process of mimicking target randomized trials using real-world data, where effective confounding control for unbiased treatment effect estimation remains a main challenge. Although various approaches have been proposed for this challenge, a systematic evaluation is still lacking. Here we emulated trials for thousands of medications from two large-scale real-world data warehouses, covering over 10 years of clinical records for over 170 million patients, aiming to identify new indications of approved drugs for Alzheimer’s disease. We assessed different propensity score models under the inverse probability of treatment weighting framework and suggested a model selection strategy for improved baseline covariate balancing. We also found that the deep learning-based propensity score model did not necessarily outperform logistic regression-based methods in covariate balancing. Finally, we highlighted five top-ranked drugs (pantoprazole, gabapentin, atorvastatin, fluticasone, and omeprazole) originally intended for other indications with potential benefits for Alzheimer’s patients.

Abstract Background Sepsis is a life-threatening organ dysfunction caused by abnormal immune responses to various, predominantly bacterial, infections. Different bacterial infections lead to substantial variation in disease manifestation and therapeutic strategies. However, the underlying cellular heterogeneity and mechanisms involved remain poorly understood. Methods Multiple bulk transcriptome datasets from septic patients with 12 types of bacterial infections were integrated to identify signature genes for each infection. Signature genes were mapped onto an integrated large single-cell RNA (scRNA) dataset from septic patients, to identify subsets of cells associated with different sepsis types, and multiple omics datasets were combined to reveal the underlying molecular mechanisms. In addition, an scRNA dataset and spatial transcriptome data were used to identify signaling pathways in sepsis-related cells. Finally, molecular screening, optimization, and de novo design were conducted to identify potential targeted drugs and compounds. Results We elucidated the cellular heterogeneity among septic patients with different bacterial infections. In Escherichia coli (E. coli) sepsis, 19 signature genes involved in epigenetic regulation and metabolism were identified, of which DRAM1 was demonstrated to promote autophagy and glycolysis in response to E. coli infection. DRAM1 upregulation was confirmed in an independent sepsis cohort. Further, we showed that DRAM1 could maintain survival of a pro-inflammatory monocyte subset, C10_ULK1, which induces systemic inflammation by interacting with other cell subsets via resistin and integrin signaling pathways in blood and kidney tissue, respectively. Finally, retapamulin was identified and optimized as a potential drug for treatment of E. coli sepsis targeting the signature gene, DRAM1, and inhibiting E. coli protein synthesis. Several other targeted drugs were also identified in other types of sepsis, including nystatin targeting C1QA in Neisseria sepsis and dalfopristin targeting CTSD in Streptococcus viridans sepsis. Conclusion Our study provides a comprehensive overview of the cellular heterogeneity and underlying mechanisms in septic patients with various bacterial infections, providing insights to inform development of stratified targeted therapies for sepsis.

Abstract Background Human leucocyte antigen (HLA)-DR plays a crucial role in the immune response against hepatitis B virus (HBV). We aimed to investigate the associations of HLA-DR single nucleotide polymorphisms (SNPs) with the generation of hepatocellular carcinoma (HCC)-related HBV mutations. The effects of HLA-DR SNPs and their interactions with HBV mutations on HCC risks were also determined. Methods Five HLA-DR SNPs (rs3135363, rs9268644, rs35445101, rs24755213, and rs984778) were genotyped in 792 healthy controls, 586 chronic hepatitis B (CHB) patients, 536 liver cirrhosis (LC) patients, and 1500 HCC patients using quantitative PCR. Sanger sequencing was used to identify the HBV mutations. Logistic regression model was performed to evaluate the association of HLA-DR SNPs with HCC risk and the frequencies of HCC-related HBV mutations. Results The variant genotypes at rs3135363, rs9268644, rs35445101, rs24755213, and rs984778 were associated with decreased HCC risks. In genotype C HBV-infected subjects, variant genotypes of these SNPs were associated with decreased frequencies of HCC-related HBV mutations such as C1653T, T1674C/G, G1719T, T1753A/C, A1762T/G1764A, A1846T, G1896A, G1899A, and preS deletion. AG genotype at rs3135363, CA genotype at rs9268644, and AG genotype at rs24755213 reduced the generation of T1753A/C and G1896A in genotype B HBV-infected subjects, respectively. In addition, the interactions of rs3135363, rs9268644, rs24755213 with C1653T, T1753A/C, A1846T, and G1896A decreased the risks of HCC. Conclusions HLA-DR genetic polymorphisms might predispose the host to immunoselection of HCC-related HBV mutations and affect the HCC risks possibly through interacting with HBV mutations.

Abstract Background To improve early diagnosis and chemotherapy efficacy monitoring in primary central nervous system lymphoma (PCNSL), cerebrospinal fluid (CSF) exosomal microRNA (miRNA) studies were performed. Method Small RNA sequencing was performed to identify candidate exosomal miRNAs as CSF biopsy biomarkers from two patients with de novo PCNSL and two patients in remission after chemotherapy. miR-200c and miR-141 expression in CSF exosomes was further validated using relative quantitative real-time polymerase chain reaction in patients with PCNSL (n = 20), patients with other neurological diseases (n = 10), and normal subjects (n = 10). Receiver operating characteristic (ROC) curve analyses of miR-200c and miR-141 in the diagnosis and prediction of chemotherapy efficacy in PCNSL were performed in patients treated with methotrexate. Additionally, bioinformatics tools were utilized to predict the potential targets of miR-200c and miR-141. Results Exosomal miR-200c and miR-141 levels in CSF from patients with PCNSL were significantly lower than those in control subjects. Importantly, miR-200c and miR-141 were upregulated in patients with PCNSL after chemotherapy (P = 0.002). There was a significant correlation between the levels of miR-141 and IL-10 in CSF (P = 0.04). The combination of miR-200c and miR-141 yielded an area under the ROC curve of 0.761 for distinguishing PCNSL with sensitivity and specificity of 60.0% and 96.7%, respectively. The potential target genes of miR-200c and miR-141 in PCNSL included ATP1B3, DYNC1H1, MATR3, NUCKS1, ZNF638, NUDT4, RCN2, GNPDA1, ZBTB38, and DOLK. Conclusion Collectively, miR-200c and miR-141 are likely to be upregulated in CSF exosomes after chemotherapy in patients with PCNSL, highlighting their potential as reliable liquid biopsy biomarkers for PCNSL diagnosis and chemotherapy efficacy monitoring.

Abstract Verticillium dahliae is a soil-borne hemibiotrophic fungal pathogen that threatens cotton production worldwide. In this study, we assemble the genomes of two V. dahliae isolates: the more virulence and defoliating isolate V991 and nondefoliating isolate 1cd3-2. Transcriptome and comparative genomics analyses show that genes associated with pathogen virulence are mostly induced at the late stage of infection (Stage II), accompanied by a burst of reactive oxygen species (ROS), with upregulation of more genes involved in defense response in cotton. We identify the V991-specific virulence gene SP3 that is highly expressed during the infection Stage II. V. dahliae SP3 knock-out strain shows attenuated virulence and triggers less ROS production in cotton plants. To control the disease, we employ polyethyleneimine-coated MXene quantum dots (PEI-MQDs) that possess the ability to remove ROS. Cotton seedlings treated with PEI-MQDs are capable of maintaining ROS homeostasis with enhanced peroxidase, catalase, and glutathione peroxidase activities and exhibit improved tolerance to V. dahliae. These results suggest that V. dahliae trigger ROS production to promote infection and scavenging ROS is an effective way to manage this disease. This study reveals a virulence mechanism of V. dahliae and provides a means for V. dahliae resistance that benefits cotton production.

Prosocial behaviour is a bedrock of humane societies. Although previous studies have shown that parental style is an important contributing factor for children's prosocial behaviour, the psychological mechanism underlying this association in specific cultural background remains unclear. Based on the ecological systems theory, this study sought to explore the influence of parental warmth on children's prosocial behaviour, and the mediating effect of self-efficacy, as well as the moderating role of teachers' incentive evaluation in the link between self-efficacy and children's prosocial behaviour. This cross-sectional, survey-based study collected data from parents and teachers of 414 Chinese preschoolers (5–6 years old). Parents of these children finished questionnaires on the Chinese version of the short-form Egna minnen av. Barndoms uppfostran (s-EMBU-C), Child Behaviour Scale (CBS), and the revised General Self-efficacy Scale (GSES), while Incentive evaluation questionnaire was finished by their teachers. Results indicated that children who experience high parental warmth were more likely to act prosocially (b = 0.61, p

To analyze self-lubricating mechanism of copper-based graphite composites, the discrete element method (DEM) was used to study motion law of graphite particles of copper-based graphite composite/45 steel during friction. The research results show the film-forming particle layer was formed on the composite surface after a period of friction, which maintained dynamic balance depends on continuous supply of graphite in the composite. At different position, the trajectory of graphite particles is different, but the motion tendency of the graphite is the same, that is, the graphite x movement direction is consistent with the sliding direction of 45 steel, the graphite y movement direction is from the inside of the composite to the friction interface, and the motion displacement in y direction is greater than that in x direction. The load and sliding speed have an important influence on the motion law of graphite. Load or speed change the trajectory of graphite particles. However, the load and speed did not change the movement trend of graphite particles, which were consistent with motion trend at different position.

Objective Immunocompromised individuals, particularly HIV patients, worldwide are at risk from cryptococcal infection. There are a number of videos of cryptococcal infection and more and more individuals may search these videos, but the quality of videos on YouTube is unclear. This study set out to assess the content and quality of YouTube videos regarding cryptococcal infection. Methods The keywords “ Cryptococcus, ” “Cryptococcosis” and “Cryptococcal infection” were searched on YouTube. The videos were evaluated and graded by two impartial raters. A 14-point content score was used to categorize videos as bad, good or exceptional. The reliability and quality were evaluated utilizing the DISCERN instrument and a 5-point global quality score. Videos were then divided into groups based on uploading sources and content types. Results A total of 46 videos were located, and the ratings provided by the two raters were identical. Our scoring algorithm determined that 54.3% (n = 25), 32.6% (n = 15) and 13.0% (n = 6) of the videos were poor, decent and exceptional, respectively. Regarding quality, no difference was identified between the various video categories. The global quality scale, number of views, days posted, content score and DISCERN showed a significant positive relationship. Conclusions Professional individuals or healthcare organizations should be encouraged to submit high-quality videos for the expanding internet population, as only a small proportion of available videos had exceptional quality.

BackgroundOxidative Balance Score (OBS) is a tool for assessing the oxidative stress-related exposures of diet and lifestyle. The study aimed to investigate the association between OBS and low muscle mass.MethodsOverall, 6,307 individuals over the age of 18 were assessed using data from the 2011 to 2018 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression and models were used, together with adjusted models.ResultsThere was a negative relationship between OBS and low muscle mass [odds ratio (OR): 0.96, 95% confidence interval (CI): 0.94–0.97, p< 0.0001] using the first OBS level as reference. The values (all 95% CI) were 0.745 (0.527–1.054) for the second level, 0.650 (0.456–0.927) for the third level, and 0.326 (0.206–0.514) for the fourth level (P for trend

IntroductionAdolescent suicide is a prevalent issue globally, with various factors contributing to this phenomenon. This study aimed to investigate these factors and their interrelationships to better understand the causes of adolescent suicide and provide evidence for its prevention.MethodsThis study conducted among middle school students in Liaoning Province, China, from April to May 2016, A cross-sectional survey was administered to 1,028 students aged 10–19, using instruments such as the Behavior Questionnaire-Revised (SBQ-R), Children's Perception of Interparental Conflict Scale (CPIC), and revised version of Inventory of Parent Attachment (IPPA-R).ResultBinary logistic regression analysis revealed that adolescents aged 15–19, adolescents with strong perceptions of parental conflict were at high risk of suicide intention. Adolescents living in rural areas, adolescents with high mother-child attachment, adolescents with high father-child attachment were at low risk of suicide intention. Furthermore, parent-child attachment played a mediating role between two dimensions of parental conflict perception (resolved situations and response effect) and suicide intention.DiscussionThe study concludes that adolescents living in urban areas, older adolescents, adolescents with a high level of parental conflict intensity, and those with low levels of parent-child attachment are at high risk of suicide intention. parent-child attachment played a mediating role between two dimensions of parental conflict perception (resolved situations and response effect) and suicide intention. Interventions aimed at reducing family conflicts and improving parent-child relationships are recommended to decrease the incidence of adolescent suicide.

CDK8 is an important member of the cyclin-dependent kinase family associated with transcription and acts as a key “molecular switch” in the Mediator complex. CDK8 regulates gene expression by phosphorylating transcription factors and can control the transcription process through Mediator complex. Previous studies confirmed that CDK8 is an important oncogenic factor, making it a potential tumor biomarker and a promising target for tumor therapy. However, CDK8 has also been confirmed to be a tumor suppressor, indicating that it not only promotes the development of tumors but may also be involved in tumor suppression. Therefore, the dual role of CDK8 in the process of tumor development is worth further exploration and summary. This comprehensive review delves into the intricate involvement of CDK8 in transcription-related processes, as well as its role in signaling pathways related to tumorigenesis, with a focus on its critical part in driving cancer progression.

Researchers have increasingly considered approaches to learning (ATL) a key indicator of school readiness. Our study purposed to examine the impacts of parental warmth on children’s approaches to learning, and the mediating role of self-efficacy, as well as the moderating role of teacher-child closeness in this relationship. Using a whole-group sampling method, 414 Chinese children aged 5–6 years participated this research together with their parents and teachers. Parents of those children were asked to fill out in person questionnaires on parental warmth, children’s approaches to learning, and self-efficacy. Children’s teachers completed the questionnaire regarding teacher-child closeness. Results indicated that children with high parental warmth were more likely to get high approaches to learning and their self-efficacy played a partial mediating role in this link. In addition, teacher-child closeness moderated the correlation between parental warmth and children’s self-efficacy. Specifically, the association between parental warmth and children’s self-efficacy was stronger for children with high teacher-child closeness than those with low teacher-child closeness. The results extend our understanding of how parental warmth affects children’s approaches to learning, revealing that strategies that could enhance self-efficacy would be effective in improving children’s approaches to learning.

Sepsis is a multi-organ dysfunction characterized by an unregulated host response to infection. It is associated with high morbidity, rapid disease progression, and high mortality. Current therapies mainly focus on symptomatic treatment, such as blood volume supplementation and antibiotic use, but their effectiveness is limited. Th17/Treg balance, based on its inflammatory property, plays a crucial role in determining the direction of the inflammatory response and the regression of organ damage in sepsis patients. This review provides a summary of the changes in T-helper (Th) 17 cell and regulatory T (Treg) cell differentiation and function during sepsis, the heterogeneity of Th17/Treg balance in the inflammatory response, and the relationship between Th17/Treg balance and organ damage. Th17/Treg balance exerts significant control over the bloom and wanes in host inflammatory response throughout sepsis.

Protocatechualdehyde (PA) is a phenolic acid present in many plants and has many biological activities. Herein, the antagonistic effects and the action mechanism of PA against methicillin-resistant Staphylococcus aureus (MRSA) were studied. The results showed that PA had both significant antibacterial and anti-biofilm activities against MRSA. Additionally, PA had synergy with ampicillin against MRSA. It was elucidated that PA was prominent in destroying cell membranes, increasing cell membrane permeability and intracellular ROS production, thus leading to bacterial cell damage. Transcriptome analysis showed that PA disrupts many physiological pathways, including increasing cell membrane permeability, inhibiting biofilm formation, decreasing resistance to antimicrobial agents, and impairing DNA replication. Finally, the antimicrobial preservation test showed that PA could inhibit the growth of MRSA and prevent the corruption of beef. In summary, PA is an effective natural antibacterial substance and has a good application potential in food preservation, even in tackling antibiotic resistance problems.

Abstract Hypertrophic scar (HS), which results from prolonged inflammation and excessive fibrosis in re‐epithelialized wounds, is one of the most common clinical challenges. Consequently, sophisticated transdermal transfersome nanogels (TA/Fu‐TS) are prepared to control HS formation by synergistically inhibiting inflammation and suppressing fibrosis. TA/Fu‐TSs have unique structures comprising hydrophobic triamcinolone acetonide (TA) in lipid multilayers and hydrophilic 5‐fluorouracil in aqueous cores, and perform satisfactorily with regard to transdermal co‐delivery to macrophages and HS fibroblasts in emerging HS tissues. According to the in vitro/vivo results, TA/Fu‐TSs not only promote macrophage phenotype‐switching to inhibit inflammation by interleukin‐related pathways, but also suppress fibrosis to remodel extracellular matrix by collagen‐related pathways. Therefore, TA/Fu‐TSs overcome prolonged inflammation and excessive fibrosis in emerging HS tissues, and provide an effective therapeutic strategy for controlling HS formation via their synergy of macrophage phenotype‐switching and anti‐fibrosis effect.

Abstract Background Epidemiology is considered to be the fundamental science of public health and plays an important role in clinical competence and professional development. The objective of this study is to evaluate the effectiveness of a short-term course for the teaching of epidemiology, which was designed as a community-based class for medical students. Method This course was designed according to Kern’s six-step approach to curriculum development. A total of 75 undergraduates were recruited. Forty-one students were assigned to an experimental group engaged in theoretical teaching and practical courses, while 34 students were assigned to the control group only taking theoretical courses. All participants were asked to complete a pre- and post-course survey and to take a test after completing the course. The scores between the experimental and control groups were compared using the Wilcoxon test. Result The experimental group showed significantly higher self-assessment scores in course understanding (p = 0.0126) and clinical practice skills (p = 0.0005) after completing the course, while no significant difference was observed in the control group. In addition, students in the experimental group reported significantly higher interest (p = 0.0015), stronger learning motivation (p = 0.0113) and a better mastery of epidemiology (p = 0.0167) after completing the course than those in the control group. However, test scores (p = 0.0859) and pass rates (p = 0.1755) demonstrated no statistical significance between the two groups. Conclusion The short-term practical course in epidemiology exerted significantly positive effects on the improvement of student learning enthusiasm, course understanding and clinical practice skills. These findings provide new ideas and statistical evidence for the development of epidemiological instruction. Future studies should explore how to more widely and optimally apply community-based courses to the teaching of epidemiology.

Abstract PACS1 syndrome is a neurodevelopmental disorder (NDD) caused by a recurrent de novo missense mutation in PACS1 (p.Arg203Trp (PACS1R203W)). The mechanism by which PACS1R203W causes PACS1 syndrome is unknown, and no curative treatment is available. Here, we use patient cells and PACS1 syndrome mice to show that PACS1 (or PACS-1) is an HDAC6 effector and that the R203W substitution increases the PACS1/HDAC6 interaction, aberrantly potentiating deacetylase activity. Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization. The dendrites, however, are beset with varicosities, diminished spine density, and fewer functional synapses, characteristic of NDDs. Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex, suggesting that targeting PACS1R203W/HDAC6 may be an effective therapy for PACS1 syndrome.

Abstract The identification of key regulatory factors that control osteoclastogenesis is important. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the complexities of circRNA expression as well as the extent of their regulatory functions during osteoclastogenesis have yet to be revealed. Here, based on circular RNA sequencing data, we identified a circular RNA, circFam190a, as a critical regulator of osteoclast differentiation and function. During osteoclastogenesis, circFam190a is significantly upregulated. In vitro, circFam190a enhanced osteoclast formation and function. In vivo, overexpression of circFam190a induced significant bone loss, while knockdown of circFam190a prevented pathological bone loss in an ovariectomized (OVX) mouse osteoporosis model. Mechanistically, our data suggest that circFam90a enhances the binding of AKT1 and HSP90β, promoting AKT1 stability. Altogether, our findings highlight the critical role of circFam190a as a positive regulator of osteoclastogenesis, and targeting circFam190a might be a promising therapeutic strategy for treating pathological bone loss.

Abstract Background Circular RNAs (circRNAs) are important regulators on the onset and progression of rheumatoid arthritis (RA). Our purpose is to explore the role and underpin mechanism of circ_0000396 in RA progression. Methods RA patients (n = 39) and healthy volunteers (n = 33) were recruited from the Affiliated Hospital of Shaanxi University of Chinese Medicine for the present work. Circ_0000396, microRNA-574-5p (miR-574-5p) and R-spondin 1 (RSPO1) RNA levels were analyzed by reverse transcription-quantitative polymerase chain reaction. Cell proliferation was analyzed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and 5-ethynyl-2′-deoxyuridine (EDU) assay. Cell apoptosis was assessed by flow cytometry. Protein expression levels of proliferating cell nuclear antigen (PCNA), Cyclin D1, Cyclin E1, BCL2-associated × protein (Bax), B-cell lymphoma-2 (Bcl2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and RSPO1 were detected by western blot assay. Enzyme-linked immunosorbent assay (ELISA) was conducted to analyze the secretion of pro-inflammatory cytokines including IL-1β and TNF-α. The interaction between miR-574-5p and circ_0000396 or RSPO1 was confirmed by dual-luciferase reporter assay and RNA-pull down assay. Results Circ_0000396 expression was notably down-regulated in RA patients compared with healthy controls. Circ_0000396 overexpression suppressed the proliferation and inflammatory response and triggered the apoptosis of RA synovial fibroblasts (RASFs), accompanied by decreases in PCNA, Cyclin D1, Cyclin E1, Bcl2, IL-1β and TNF-α protein expression and an increase in Bax protein expression. Circ_0000396 acted as a molecular sponge for miR-574-5p, and circ_0000396 overexpression-mediated protective effects on RASFs dysfunction were largely reversed by the introduction of miR-574-5p mimics. miR-574-5p interacted with the 3’ untranslated region (3’UTR) of RSPO1, and miR-574-5p negatively regulated RSPO1 expression in RASFs. Circ_0000396 could up-regulate the expression of RSPO1 by sponging miR-574-5p in RASFs. RSPO1 interference largely overturned circ_0000396 overexpression-mediated effects in RASFs. Conclusion Circ_0000396 restrained the proliferation and inflammation and induced the apoptosis of RASFs by mediating miR-574-5p/RSPO1 axis, which provided novel potential targets for RA treatment.

The aim of this study was to perform a molecular diagnosis of hemophilia A (HA) among patients in the Shanxi Province of China. Fifty-two HA patients were tested, including IVS22 (31 samples), IVS1 (3 samples), missense (11 samples), nonsense (3 samples), and 4 cases of frameshift (2 cases of deletion, 1 case of insertion, 1 case of single-base duplication). With the exception of the single-base G duplication variant (p.Ile1213Asnfs*28), this was the hotspot variant reported by research groups at an early stage. The remaining variants were found, for the first time, in the region. The missense variants p.Cys172Ser, p.Tyr404Ser, p.Asp1903Gly, and p.Ser2284Asn, the deletion variant p.Leu2249fs*9, and the insertion variant p.Pro2319fs*97 were novel variants. The application of next-generation sequencing (NGS) molecular diagnosis enriched the variant spectrum of HA, which is greatly significant for individualized genetic counseling, clinical diagnosis, and treatment. NGS and a variety of bioinformatics prediction methods can further analyze the impact of genetic variation on protein structure or function and lay the foundation to reveal the molecular pathogenic mechanism of novel variants.

Abstract Cellulose, as a component of green plants, becomes attractive for fabricating biocompatible flexible functional devices but is plagued by hydrophilic properties, which make it easily break down in water by poor mechanical stability. Here we report a class of SiO2-nanoparticle-decorated bacteria-cellulose meta-skin with superior stability in water, excellent machining property, ultrathin thickness, and active bacteria-repairing capacity. We further develop functional ultrasonic metasurfaces based on meta-skin paper-cutting that can generate intricate patterns of ~10 μm precision. Benefited from the perfect ultrasound insulation of surface Cassie-Baxter states, we utilize meta-skin paper-cutting to design and fabricate ultrathin (~20 μm) and super-light (